Remyelinating drug Saving nerves

Wootla B, Denic A, Warrington AE, Rodriguez M.A monoclonal natural human IgM protects axons in the absence of remyelination. J Neuroinflammation. 2016 ;13(1):94.
BACKGROUND:Whereas demyelination underlies early neurological symptoms in multiple sclerosis (MS), axonal damage is considered critical for permanent chronic deficits. Intracerebral infection of susceptible mouse strains with Theiler’s murine encephalomyelitis virus (TMEV) results in chronic induced demyelinating disease (TMEV-IDD) with progressive axonal loss and neurologic dysfunction similar to progressive forms of MS. We previously reported that treatment of chronic TMEV-IDD mice with a neurite outgrowth-promoting natural human antibody, HIgM12, improved brainstem NAA concentrations and preserved functional motor activity. In order to translate this antibody toward clinical trial, we generated a fully human recombinant form of HIgM12, rHIgM12, determined the optimal in vivo dose for functional improvement in TMEV-IDD, and evaluated the functional preservation of descending spinal cord axons by retrograde labeling.
FINDINGS: SJL/J mice at 45 to 90 days post infection (dpi) were studied. A single intraperitoneal dose of 0.25 mg/kg of rHIgM12 per mouse is sufficient to preserve motor function in TMEV-IDD. The optimal dose was 10 mg/kg. rHIgM12 treatment protected the functional transport in spinal cord axons and led to 40 % more Fluoro-Gold-labeled brainstem neurons in retrograde transport studies. This suggests that axons are not only present but also functionally competent. rHIgM12-treated mice also contained more mid-thoracic (T6) spinal cord axons than controls.
CONCLUSIONS:This study confirms that a fully human recombinant neurite outgrowth-promoting monoclonal IgM is therapeutic in a model of progressive MS using multiple reparative readouts. The minimum effective dose is similar to that of a remyelination-promoting monoclonal human IgM discovered by our group that is presently in clinical trials for MS.

The TMEV model has been a model of viral induced demyelination and now it is claimed that it is a model of progressive MS. I am not sure on what grounds. It has nerve loss?

This study says that one delivery of antibody stops 40% nerve loss, which sounds great. If they had done more the mouse’s immune system would have got rid of it, but one injection and it saves the brain..great 

Maybe it is time that this approach was put to the test. One injection should be all that is needed. 

I first saw this approach well over a decade ago and we are still awaiting the human results.

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  • Hi MD. Do you think that these remyelinating therapies will have a finite treatment term or be a lifelong therapy?

    Is there evidence that remyelinating therapies reverse the cellular dysfunction in axons/neurons-like mitochondrial dysfunction, Na channel addition and Ca channels with Ca reflux and subsequent apoptosis? I only found one article on PubMed that showed remyelination increased the number of mitochondria in a dysfunctional neuron.

    If remyelinating agents do succeed, will they be neuroprotective? Do you still think that the neuroprotectants, like anti-seizure Na channel blockers, Laquimod etc, will still have a place in treatment of MS? Obviously, efficacious DMDs will still need to be taken, as we still have not found the offending agent that has heightened the MS immune system in the first place.

    • you think that these remyelinating therapies will have a finite treatment term or be a lifelong therapy. Unless you get your MS under control you will need to repeated take these agents, but I suspect once you have the oligos remyelinating you would would not need to keep taking, however this question has not been adequately addresseed even experimentally.

      They should be neuroprotective and there is support for this from the Trapp Lab and as for neuroprotectives you have to keep the nerves going whilst remyelination takes place and so far remyelination has only been shown in recently demyelinated lesions, remyelinating chronic demyelinated lesions has not been shown experimentally or clinically and if clamestine/anti-LINGO was doing this I suspect the outcomes of trials would have been more dramatic.

    • Regarding "… far remyelination has only been shown in recently demyelinated lesions, remyelinating chronic demyelinated lesions has not shown experimentally or clinically…", the research has shown there are inhibitory components to the astrogliotic scar of chronic lesions. The inhibitory environment has to be addressed before remyelination.



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